Longitudinal Progression of Cognitive Decline Correlates with Changes in the Spatial Pattern of Brain ¹⁸F-FDG PET

Abstract

Evaluating the symptomatic progression of mild cognitive impairment (MCI) caused by Alzheimer disease (AD) is practically accomplished by tracking performance on cognitive tasks, such as the Alzheimer Disease Assessment Scale’s cognitive subscale (ADAS_cog), the Mini-Mental Status Examination (MMSE), and the Functional Activities Questionnaire (FAQ). The longitudinal relationships between cognitive decline and metabolic function as assessed using 18F-FDG PET are needed to address both the cognitive and the biologic progression of disease state in individual subjects. We conducted an exploratory investigation to evaluate longitudinal changes in brain glucose metabolism of individual subjects and their relationship to the subject’s changes of cognitive status. Methods We describe a method to determine correlations in 18F-FDG spatial distribution over time. This parameter is termed the regional 18F-FDG time correlation coefficient (rFTC). By using linear mixed-effects models, we determined the difference in the rFTC decline rate between controls and subjects at high risk of developing AD, such as individuals with MCI or the presence of apolipoprotein E (APOE)–ε4 allele. The association between each subject’s rFTC and performance on cognitive tests (ADAS_cog, MMSE, and FAQ) was determined with 2 different correlation methods. All subject data were downloaded from the Alzheimer Disease Neuroimaging Initiative. Results The rFTC values of controls remained fairly constant over time (−0.003 annual change; 95% confidence interval, −0.010– 0.004). In MCI patients, the rFTC declined faster than in controls by an additional annual change of −0.02 (95% confidence interval, −0.030 to −0.010). In MCI patients, the decline in rFTC was associated with cognitive decline (ADAS_cog, P = 0.011; FAQ, P = 0.0016; MMSE, P = 0.004). After a linear effect of time was accounted for, visit-to-visit changes in rFTC correlated with visit-to-visit changes in all 3 cognitive tests. Conclusion Longitudinal changes in rFTC detect subtle metabolic changes in individuals associated with variations in their cognition. This analytic tool may be useful for a patient-based monitoring of cognitive decline.

Alterations in mitochondrial number and function in Alzheimer’s disease fibroblasts

“…Neuronal mitochondrial dysfunction is an early and prominent feature of AD (Wang 2009) as is reduced energy metabolism in the AD brain (Landau 2011, Shokouhi 2013, Yamane 2013). Diminished neuronal expression of genes encoding subunits of the ETC, as well as decreased expression or activity of many enzymes involved in oxidative metabolism, are also well-documented in AD brains (Cottrell 2001, Gibson 1998, Nagy 1999, Parker 1994).…”

MicroPET imaging and transgenic models: a blueprint for Alzheimer's disease clinical research

“…Although hypometabolism is an early abnormality in AD, the link between amyloidosis, tau pathology, and metabolic decline remains elusive [16]. Although glucose hypometabolism correlates with cognitive decline in humans [95], such associations remain unclear in animal models. Glucose metabolism abnormalities indexed by [ 18 F]FDG uptake have been reported either during the resting state or as a result of sensory or motor activation.…”

Longitudinal Positron Emission Tomography in Preventive Alzheimer's Disease Drug Trials, Critical Barriers from Imaging Science Perspective

“…Both Aβ-PET and FDG-PET are used in AD drug trials. Current longitudinal FDG-PET findings correlate well with clinical outcomes and cognitive tests of subjects with Alzheimer’s dementia and mild cognitive impairment (44, 73, 78). There is a need for imaging studies that can find similar associations between PET measures and subtle cognitive alterations in normal\preclinical AD population.…”

“…Some of the FDG-PET related critical barriers were addressed in our previous studies where we developed a new technique for FDG-PET analysis, the regional FDG-PET time correlation coefficient (rFTC) (73) that measures similarities (correlations) between subject’s serial scans. The correlation analysis can be performed on clinically acquired PET data (short static PET scans) and the correlation decline can be used as a marker of metabolic changes occurring anywhere in the brain.…”